ClinVar Genomic variation as it relates to human health

The VHL c.492G>C; p.Gln164His variant has been described in several individuals affected with pheochromocytoma and/or paraganglioma (Bauters 2003, Buffet 2012, McInerney-Leo 2014) and is observed on only 2 alleles in the Genome Aggregation Database. The glutamine at codon 164 is highly conserved but computational algorithms (PolyPhen-2: damaging, SIFT: tolerated) are inconclusive on the effect of this variant on protein structure and/or function. However, this variant occurs in a region that is critical for binding to elongin B and elongin C (Kishida 1995, Ohh 1999). Additionally, another variant at this codon (c.491A>G; p.Gln164Arg) has been reported in individuals affected with pheochromocytoma and/or paraganglioma and is considered pathogenic (Buffet 2012, Sovinz 2010). Based on available information, this variant is considered likely pathogenic. References: Bauters C et al. Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes. J Med Genet. 2003 Jun;40(6):e75. Buffet A et al. A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm Metab Res. 2012 May;44(5):359-66. Kishida T et al. Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res. 1995 Oct 15;55(20):4544-8. McInerney-Leo A et al. Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clin Endocrinol (Oxf). 2014 Jan;80(1):25-33. Ohh M et al. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999 Dec;104(11):1583-91. Sovinz P et al. Pheochromocytoma in a 2.75-year-old-girl with a germline von Hippel-Lindau mutation Q164R. Am J Med Genet A. 2010 Jul;152A(7):1752-5.

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 164 of the VHL protein (p.Gln164His). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 12807974, 17392848, 19215943, 22517557, 24102379, 29891534; Invitae). ClinVar contains an entry for this variant (Variation ID: 618485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17392848, 22517557, 24102379, 29891534; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The p.Q164H variant (also known as c.492G>C), located in coding exon 3 of the VHL gene, results from a G to C substitution at nucleotide position 492. The glutamine at codon 164 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a 47-year-old female with an abdominal paraganglioma (PGL) and a family member with unilateral pheochromocytoma (PCC) at age 39 (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75). In addition, a different nucleotide change at the same position (VHL c.492G>T) causing the same amino acid change has been identified in a patient with capillary retinal angioma (Kreusel KM et al. Can. J. Ophthalmol. 2007 Apr;42:251-5; McInerney-Leo AM et al. Clin. Endocrinol. (Oxf) 2014 Jan;80:25-33) and several patients with either PGL or PCC (Meyer-Rochow GY et al. J. Surg. Res. 2009 Nov;157:55-62; Buffet A et al. Horm. Metab. Res. 2012 May;44:359-66). Internal structural analysis indicates this alteration disrupts the fold of the elongin binding domain of VHL (Ambry internal data; Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with VHL-related cancers (Bauters et al., 2003; Meyer-Rochow et al., 2009; McInerney-Leo et al., 2014); This variant is associated with the following publications: (PMID: 24102379, 22517557, 19215943, 29891534, 17392848, 12807974)